The discovery of β-arrestin-dependent GPCR signaling has led to an exciting new field in GPCR pharmacology: to develop “biased agonists” that can selectively target a specific downstream signaling pathway that elicits beneficial therapeutic effects without activating other pathways that elicit negative side effects. This new trend in GPCR drug discovery requires us to understand the structural and molecular mechanisms of β-arrestin-biased agonism, which largely remain unclear. We have used cutting-edge mass spectrometry (MS)-based proteomics, combined with systems, chemical and structural biology to study protein function, macromolecular interaction, protein expression and posttranslational modifications in the β-arrestin-dependent GPCR signaling. These high-throughput proteomic studies have provided a systems view of β-arrestin-biased agonism from several perspectives: distinct receptor phosphorylation barcode, multiple receptor conformations, distinct β-arrestin conformations, and ligand-specific signaling. The information obtained from these studies offers new insights into the molecular basis of GPCR regulation by β-arrestin and provides a potential platform for developing novel therapeutic interventions through GPCRs.

β-arrestin依赖性GPCR信号的发现导致了GPCR药理学一个令人兴奋的新领域：开发“偏向激动剂”，可以选择性地靶向特定的下游信号传导途径，该途径可以引发有益的治疗效果，而不会激活引起负面副作用的其他途径。GPCR药物发现的这一新趋势要求我们了解β-arrestin引起的激动作用的结构和分子机制，目前仍不清楚。我们已经使用了基于尖端质谱（MS）的蛋白质组学，并结合了系统，化学和结构生物学来研究蛋白质功能，大分子相互作用，蛋白质表达和β-arrestin依赖性GPCR信号传导中的翻译后修饰。这些高通量的蛋白质组学研究从多个角度提供了β-arrestin偏置激动作用的系统视图：不同的受体磷酸化条形码，多个受体构象，不同的β-arrestin构象以及配体特异性信号传导。从这些研究中获得的信息为β-arrestin调控GPCR的分子基础提供了新见识，并为通过GPCR开发新的治疗性干预措施提供了潜在平台。